Motor nerves interact with skeletal muscle in a relationship which is termed "trophic". Neurotrophic influences not only maintain the integrity of the muscle, but also determine some of its specific physiological ("slow-fast") and metabolic ("red-white") properties, and are involved in neuromuscular junction formation and maintenance. The major purpose of the proposed project is to continue and extend our analysis of these trophic relationships, based on our present concept of multiple neurotrophic factors. We will analyze the individual contributions of cholinergic transmission, muscle activity or usage, and material carried by axonal transport to well-defined, trophically-regulated properties of muscle. Further, we will study the role of axonal transport in regeneration of nerves, and in the possible delivery of macromolecular substances to muscle. We will attempt to evaluate critically the actions of the pharmacological agents used in these studies, particularly botulinum toxin. We plan to continue our investigations of clinically-related problems, including: a) Neuromuscular abnormalities in myasthenia gravis; b) The question of denervation changes in myopathies; c) The effects of aging and of experimental neuropathies on axonal transport. It is anticipated that this work will lead to a clearer understanding of the trophic influences of nerve on muscle, and of nerve-muscle interactions in related clinical disorders.